EP1684851B1 - Verfahren zur herstellung von polymeren pufferformulierungen für elektrotransport-anwendungen - Google Patents

Verfahren zur herstellung von polymeren pufferformulierungen für elektrotransport-anwendungen Download PDF

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EP1684851B1
EP1684851B1 EP04811757A EP04811757A EP1684851B1 EP 1684851 B1 EP1684851 B1 EP 1684851B1 EP 04811757 A EP04811757 A EP 04811757A EP 04811757 A EP04811757 A EP 04811757A EP 1684851 B1 EP1684851 B1 EP 1684851B1
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Prior art keywords
drug
exchange material
ion exchange
polymeric
drug solution
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French (fr)
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EP1684851A1 (de
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David Rauser
Rama Padmanabhan
Joseph B. Phipps
Janardhanan Subramony
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Alza Corp
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Alza Corp
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/08—Solutions
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61N—ELECTROTHERAPY; MAGNETOTHERAPY; RADIATION THERAPY; ULTRASOUND THERAPY
    • A61N1/00—Electrotherapy; Circuits therefor
    • A61N1/02—Details
    • A61N1/04—Electrodes
    • A61N1/0404—Electrodes for external use
    • A61N1/0408—Use-related aspects
    • A61N1/0428—Specially adapted for iontophoresis, e.g. AC, DC or including drug reservoirs
    • A61N1/0448—Drug reservoir
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A61K47/42—Proteins; Polypeptides; Degradation products thereof; Derivatives thereof, e.g. albumin, gelatin or zein
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0087—Galenical forms not covered by A61K9/02 - A61K9/7023
    • A61K9/0095—Drinks; Beverages; Syrups; Compositions for reconstitution thereof, e.g. powders or tablets to be dispersed in a glass of water; Veterinary drenches
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61N—ELECTROTHERAPY; MAGNETOTHERAPY; RADIATION THERAPY; ULTRASOUND THERAPY
    • A61N1/00—Electrotherapy; Circuits therefor
    • A61N1/02—Details
    • A61N1/04—Electrodes
    • A61N1/0404—Electrodes for external use
    • A61N1/0408—Use-related aspects
    • A61N1/0412—Specially adapted for transcutaneous electroporation, e.g. including drug reservoirs
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
    • A61P7/02—Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors

Definitions

  • the present invention relates to novel methods for preparing drug formulations for delivery by electrotransport that involve adjusting the pH of the drug formulation prior to incorporation into an electrotransport delivery system, and adding a buffering agent to the drug formulation upon incorporation into the electrotransport delivery system, wherein the buffering agent reduces changes in the pH of the drug formulation during electrotransport.
  • the delivery of active agents through the skin provides many advantages, including comfort, convenience, and non-invasiveness. In addition, gastrointestinal irritation and the variable rates of absorption and metabolism encountered in oral delivery are avoided. Transdermal delivery also provides a high degree of control over blood concentrations of any particular active agent.
  • active agents are not suitable for passive transdermal delivery because of their size, ionic charge characteristics, and hydrophilicity.
  • One method for transdermal delivery of such active agents involves the use of electrical current to actively transport the active agent into the body through intact skin, which is known as electrotransport or iontophoretic drug delivery.
  • electrotransport devices at least two electrodes are used, which are disposed so as to be in intimate electrical contact with some portion of the skin.
  • One electrode, called the active or donor electrode is the electrode from which the active agent is delivered into the body.
  • the other electrode called the counter or return electrode, serves to close the electrical circuit through the body.
  • the circuit is completed by connection of the electrodes to a source of electrical energy, and usually to circuitry capable of controlling the current passing through the device. If the ionic substance to be driven into the body is positively charged, then the positive electrode (the anode) will be the active electrode and the negative electrode (the cathode) will serve as the counter electrode. If the ionic substance to be delivered is negatively charged, then the cathodic electrode will be the active electrode and the anodic electrode will be the counter electrode.
  • Electrotransport devices also require a reservoir or source of the active agent that is to be delivered or introduced into the body. Such reservoirs are connected to the anode or the cathode of the electrotransport device to provide a fixed or renewable source of one or more desired active agents.
  • oxidation of a chemical species takes place at the anode while reduction of a chemical species takes place at the cathode.
  • Both of these reactions generate a mobile ionic species with a charge state like that of the active agent in its ionic form.
  • Such mobile ionic species are referred to as competitive species or competitive ions because the species compete with the active agent for delivery by electrotransport.
  • transdermal electrotransport flux of a cationic species is optimized when the pH of the donor solution is about 4 to about 10, more preferably about 5 to about 8, and most preferably about 6 to about 7.
  • transdermal electrotransport flux of an anionic species is optimized when the pH of the donor solution is about 2 to about 6, and more preferably about 3 to about 5.
  • a problem that arises with the addition of pH-altering species (e.g., an acid or a base) to the active agent solution in an electrotransport device is that extraneous ions having the same charge as the active agent are introduced into the solution. These ions generally compete with the active agent ions for electrotransport through the body surface.
  • pH-altering species e.g., an acid or a base
  • extraneous ions having the same charge as the active agent are introduced into the solution.
  • These ions generally compete with the active agent ions for electrotransport through the body surface.
  • sodium hydroxide to raise the pH of a cationic active agent-containing solution will introduce sodium ions into the solution that will compete with the cationic active agent for delivery by electrotransport into the patient, thereby making the electrotransport delivery less efficient, i.e., less active agent will be delivered per unit of electrical current applied by the device.
  • the invention relates to methods for preparing compositions for use in an electrotransport delivery system that comprise providing a drug solution comprising drug ions and associated counterions; adjusting the pH of the drug solution by contacting the drug solution with a first ion exchange material; separating the first ion exchange material from the pH-adjusted drug solution; adding the pH-adjusted drug solution to a reservoir of an electrotransport delivery system; and contacting the pH-adjusted drug solution with a second ion exchange material.
  • the drug ions are cationic, the associated counterions are anionic, the first ion exchange material is a polymeric anion exchange material, and the second ion exchange material is a polymeric anion or cation exchange material.
  • the drug ions are anionic, the associated counterions are cationic, the first ion exchange material is a polymeric cation exchange material, and the second ion exchange material is a polymeric cation or anion exchange material.
  • Figure 1 depicts the chemical structure of Compound 1, a 2-[3-[4-(4-piperidinyloxy)anilino]-1propenyl]benzamidine derivative.
  • Figure 2 depicts the iontophoretic flux of Compound 1 across heat-separated human epidermis (0.1 mA/cm 2 ) from hydrogels loaded with a solution of Compound 1 pH-adjusted with either a polymeric resin or NaOH.
  • Figure 3 depicts buffering in hydrogels containing polacrilin and Compound 1.
  • adjusting refers to changing by any measurable degree the pH of a solution or substance.
  • contacting refers to any means that directly or indirectly cause placement together of moieties, such that the moieties come into physical contact with each other. Contacting thus includes physical acts such as placing the moieties together in a container, combining the moieties, or mixing the moieties.
  • drug and “pharmaceutically active agent” refer to any chemical material or compound that induces a desired local or systemic effect, and can be delivered by electrotransport.
  • drug ion and “associated counterions” refer to either positively or negatively charged forms of a drug with which counterions of a charge opposite to that of the drug are associated.
  • Cationic drugs that can be used in the methods of the invention include any cationic drug that, when present in a formulation, has a first pKa, or any subsequent pKa, that is lower than the pH of the formulation buffering range.
  • the cationic drug has at least one pKa that is lower than the desired storage or electrotransport operating pH and has at least one pKa that is higher than the storage or electrotransport operating pH.
  • Examples of such cationic drugs include, but are not limited to, 2-[3-[4-(4-piperidinyloxy)anilino]-1propenyl]benzamidine derivatives such as, for example, ([3-(3-Carbamimidoyl-phenyl)-2-fluoro-allyl]- ⁇ 4-[1-(1-imino-ethyl)-piperidin-4-yloxy]-phenyl ⁇ -sulfamoyl)-acetic acid hydrochloride; ([3-(3-Carbamimidoyl-phenyl)-2-methyl-allyl]- ⁇ 4-[1-(1-imino-ethyl)-piperidin-4-yloxy]-phenyl ⁇ -sulfamoyl)-acetic acid hydrochloride; and ([3-(3-Carbamimidoyl-phenyl)-2-fluoro-allyl]- ⁇ 3-carbamoyl-4-[
  • Anionic drugs that can be used in the methods of the invention include any anionic drug that, when present in a formulation, has a first pKa, or any subsequent pKa, that is higher than the pH of the formulation buffering range.
  • the anionic drug has at least one pKa that is higher than the desired storage or electrotransport operating pH and has at least one pKa that is lower than the storage or electrotransport operating pH.
  • examples of such anionic drugs include, but are not limited to, captopril and lisinopril.
  • the terms "separating,” “separate,” and all variations thereof refer to removing substantially all of the first ion exchange material from the drug solution.
  • the terms “adding,” and “add,” and all variations thereof, refer to any means that directly or indirectly cause placement together of moieties or components, such that the moieties or components come into close proximity to each other.
  • the terms include acts such as placing the moieties or components together in a container, combining the moieties or components, contacting the moieties or components, or stirring, vortexing, or agitating the moieties or components together.
  • ion exchange resin or “ion exchange material” refer to any material comprising (i) a mobile ionic species selected from the group consisting of hydronium and hydroxyl ions, and (ii) at least one oppositely charged, substantially immobile ionic species.
  • the ion exchange materials useful in conjunction with certain embodiments of the invention are capable of donating either a hydroxyl ion (i.e., anion exchange materials or resins, which are typically used to adjust the pH of cationic drug formulations), or a hydrogen ion (i.e., cation exchange materials or resins, which are typically used to adjust the pH of anionic drug formulations).
  • electrotransport and “electrically-assisted transport” are used to refer to the delivery of drugs by means of an applied electromotive force to a drug-containing reservoir.
  • the drug can be delivered by electromigration, electroporation, electroosmosis or any combination thereof.
  • Electroosmosis has also been referred to as electrohydrokinesis, electroconvection, and electrically induced osmosis.
  • electroosmosis of a species into a tissue results from the migration of solvent in which the species is contained, as a result of the application of electromotive force to the therapeutic species reservoir, i.e., solvent flow induced by electromigration of other ionic species.
  • electrotransport and “electrically-assisted transport” refer to (1) the delivery of charged drugs by electromigration, (2) the delivery of uncharged drugs by the process of electroosmosis, (3) the delivery of charged or uncharged drugs by electroporation, (4) the delivery of charged drugs by the combined processes of electromigration and electroosmosis, and/or (5) the delivery of a mixture of charged and uncharged drugs by the combined processes of electromigration and electroosmosis.
  • electrotransport delivery system refers to any device that can be used to perform electrotransport.
  • the term "competing ions” refers to ionic species having the same sign charge as the drug to be delivered by electrotransport, and which may take the place of the drug and be delivered through the body surface.
  • conventional buffering agents used to buffer the pH of a donor reservoir solution can likewise result in the addition of competing ions into the donor reservoir, which results in lower efficiency of electrotransport drug delivery.
  • gel matrix refers to a composition, of which the reservoir of an electrotransport delivery device is generally comprised, having a viscosity of from about 1,000 to about 200,000 poise, preferably from about 5,000 to about 50,000 poise.
  • reducing refers to decreasing by any measurable degree variations in the pH of a drug solution.
  • delivering refers to the administration of a drug to a patient or test subject using electrotransport.
  • patient refers to an animal, mammal, or human being.
  • the present invention relates to methods for preparing compositions for use in electrotransport delivery systems.
  • the methods reduce changes in the pH of drug solutions during electrically assisted transport and during long-term storage without introducing competing ions that could negatively impact flux, resulting in effective delivery and stability of the drugs.
  • the methods also prevent catalysis of drugs that have poor stability outside certain pH ranges by maintaining the pH of solutions of such drugs at a desired level.
  • the methods of the invention involve a two-step process in which the pH of a drug solution is first adjusted using means that avoid the introduction of competing ions into the solution, and then a buffering agent is added to the pH-adjusted drug solution, which reduces changes in the pH of the drug solution during electrotransport or storage.
  • the buffering agent used in the second step of the process is a polymeric resin.
  • the present invention is directed to methods that involve an initial adjustment of the pH of a drug solution prior to incorporating the solution into an electrotransport drug delivery system.
  • the pH of any particular drug solution can be adjusted either upward or downward, as desired.
  • the flux of the drug through the skin can be optimized, as can the stability of particular drug/polymer matrix compositions.
  • partially or completely neutralized drug solutions can yield a higher transdermal flux than the corresponding drug salt formulation, particularly when the drug is a divalent or polyvalent species.
  • the present technique does not involve the introduction of extraneous ions into the electrotransport system that would compete with the drug ions for electrotransport through the body surface.
  • extraneous ions For example, with cationic drugs, partial or complete neutralization by admixture with potassium hydroxide, sodium hydroxide, or the like would result in the incorporation of potassium ions, sodium ions, or the like, into the drug formulation, species that would in turn compete with the cationic drug for electrotransport delivery and reduce the efficiency of drug delivery.
  • the present invention relates to methods in which the pH of a drug solution comprising drug ions and associated counterions is adjusted prior to incorporating the solution into an electrotransport drug delivery system.
  • the pH of the drug solution is adjusted by contacting the drug solution with a first ion exhange material.
  • the invention is directed to methods in which the drug ions are cationic, the associated counterions are anionic, and the first ion exchange material is a polymeric anion exchange material.
  • the first polymeric anion exchange material is a polymeric anion exchange resin or a polymeric anion exchange membrane.
  • the first ion exchange material is preferably a polymeric anion exchange material that will exchange hydroxyl ions for the negatively charged counterions typically associated with cationic drugs, e.g., chloride, bromide, acetate, trifluoroacetate, bitartrate, propionate, citrate, oxalate, succinate, sulfate, nitrate, phosphate, and the like.
  • Suitable anion exchange materials are typically the hydroxide forms of amine-containing polymers, e.g., polyvinyl amines, poly epichlorohydrin/tetraethylenetriamines, polymers containing pendant amine groups, and the like.
  • a preferred anion exchange material for use herein is a co-polymer of styrene and divinyl benzene having a quaternary ammonium functionality and an associated hydroxyl ion.
  • suitable anion exchange materials include, but are not limited to, the hydroxide forms of Amberlite TM IRA-958 (an acrylic/divinylbenzene copolymer available from Rohm and Haas), cholestyramine (a styrene/divinylbenzene copolymer also available from Rohm and Haas), Dowex 2X8 (a styrene/divinylbenzene available from Dow Chemical), and Macro-Prep High Q (an acrylic/ethyleneglycol dimethacrylate copolymer available from BioRad Laboratories).
  • anion exchange materials containing primary, secondary and tertiary amines are relatively weak bases, while those containing quaternary amine functionalities are strongly basic, and will more quickly and effectively adjust upward the pH of formulations of cationic drug salts. Accordingly, such materials are preferred for use herein.
  • the invention is directed to methods in which the drug ions are anionic, the associated counterions are cationic, and the first ion exchange material is a polymeric cation exchange material.
  • the first polymeric cation exchange material is a polymeric cation exchange resin or a polymeric cation exchange membrane.
  • the first ion exchange material used is preferably a cation exchange material that will exchange hydrogen or hydronium ions for the positively charged counterions typically associated with anionic drugs.
  • Salts of cationic drugs are usually formed by treating the free acid form of the drug with a pharmaceutically acceptable base, typically an amine such as diethylamine, triethylamine, ethanolamine, or the like, giving rise to positively charged quaternary ammonium moieties associated with the drug.
  • Cation exchange resins that will exchange hydrogen ions for such species include, for example, cation exchange resins comprising a polymer having one or more acid moieties.
  • Such polymers include, for example, polyacrylic acids, polyacrylic sulfonic acids, polyacrylic phosphoric acids and polyacrylic glycolic acids.
  • Cation exchange resins containing carboxylic acid moieties are weaker acids and are relatively more useful for buffering, while those containing functionalities such as sulfonic acids are more strongly acidic, and are accordingly preferred in connection with the present methods as providing faster and more efficient pH adjustment.
  • Cation exchange resins of weaker acids useful for buffering include Amberlite IRP-64 (from Rohm and Haas) and acrylic polymers such as Bio-Rex 70 from Biorad.
  • the preferred direction and type of pH adjustment will depend upon whether the drug is cationic, and hence delivered from an anodic reservoir, or anionic and hence delivered from a cathodic reservoir, as well as on the solubility characteristics of the particular drug to be delivered.
  • the pH of an anodic reservoir formulation is typically in the range of about 4 to about 10, more preferably in the range of about 5 to about 8, and most preferably from about 6 to about 7.
  • the pH of a cathodic reservoir is typically in the range of about 2 to about 6, more preferably in the range of about 3 to about 5.
  • ion exchange materials used as the first ion exchange material in the methods of the invention may be replaced with any relatively high molecular weight material having acid or base functionalities, such that conversion of ionized functionalities present in the drug molecule will be effected by exchange with protons or hydroxyl ions present in the material, and separation of the drug solution therefrom will be facilitated by virtue of the material's molecular weight.
  • the molecular weight of the material be at least about 200 Daltons, more preferably at least about 300 Daltons, and most preferably at least about 500 Daltons.
  • the present invention relates to methods in which the pH of a drug solution comprising drug ions and associated counterions is adjusted prior to incorporating the solution into an electrotransport drug delivery system.
  • the pH of the drug solution is adjusted by contacting the drug solution with a first ion exhange material.
  • the drug solution is contacted with the first ion exchange material by simple admixture of the first ion exchange material, typically in the form of an ion exchange resin associated with a solid support (e.g., beads or the like), with a solution of the drug salt.
  • the relative quantities of the first ion exchange material and the drug salt will depend upon the desired change in pH, which is in turn dependent upon the degree of drug salt neutralization.
  • the pH of the drug formulation will be adjusted such that the flux of the drug through the skin, during electrotransport drug delivery, is optimized. Accordingly, the preferred pH for any given drug salt formulation may be readily determined by conducting routine experimentation to evaluate optimum drug flux.
  • neutralization is generally conducted to a degree effective to convert a substantial fraction of the drug salt, typically greater than about 80%, to a monovalent form.
  • the drug is a cationic or anionic factor Xa inhibitor and an anti-coagulant.
  • the drug is a cationic benzamidine or naphthamidine derivative.
  • the drug is a cationic benzamidine derivative.
  • the drug is a 2-[3-[4-(4-piperidinyloxy)anilino]-lpropenyl]benzamidine derivative as described, for example, in Japanese Patent Number JP 2003002832 and PCT Application Publication Number WO 02/089803 , incorporated herein by reference in their entireties.
  • the drug is the 2-[3-[4-(4-piperidinyloxy)anilino]-1propenyl]benzamidine derivative depicted in Figure 1 and referred to as Compound 1.
  • the drug is an anionic drug, such as, for example, captopril or lisinopril.
  • the drug is terbutaline.
  • Divalent and polyvalent drugs that can be used in certain embodiments of the methods and compositions of the invention include, but are not limited to, alniditan, as well as talipexole dihydrochloride, carpipramine dihydrochloride, histamine dihydrochloride, proflavine dihydrochloride and gusperimus trihydrochloride.
  • the concentration of the drug in the formulations prepared by the methods of certain embodiments of the invention depends upon the delivery requirements for the drug.
  • the percent drug loading can range, for example, from about 1 % to about 30 %, more preferably from about 1.5 % to about 20 %, and more preferably from about 2 % to about 10 %.
  • Reaction between the drug solution and the first ion exchange material is typically quite fast, on the order of minutes.
  • the drug solution may be separated from the first ion exchange material using centrifugation, standard filtration techniques (e.g., filters, screens, etc.), or using a syringe and a narrow gauge (e.g., 26 gauge) needle.
  • the pH-adjusted drug solution can then be introduced into the reservoir of an electrotransport delivery system, typically by incorporation into a gel matrix material that serves as the drug reservoir.
  • Certain embodiments of the invention relate to methods for preparing compositions for use in an electrotransport delivery system in which the pH-adjusted drug solution is contacted with a second ion exchange material.
  • the pH adjusted-drug solution is first added to the reservoir of an electrotransport delivery system, and the second ion exchange material is then added to the reservoir containing the drug solution.
  • the pH-adjusted drug solution is first contacted with the second ion exchange material, and the resultant mixture is then added to the reservoir of an electrotransport delivery system.
  • the second ion exchange material is first added to the reservoir of an electrotransport delivery system, and then the pH-adjusted drug solution is added to the reservoir containing the second ion exchange material.
  • the drug ions are cationic
  • the associated counterions are anionic
  • the second ion exchange material is a polymeric anion or cation exchange material.
  • the choice of the appropriate second polymeric ion exchange resin is determined by the acid/base properties of the resin.
  • a polymeric anion exchange material provides the desired properties
  • a polymeric cation exchange material provides the desired properties.
  • the drug ions are anionic
  • the associated counterions are cationic
  • the second ion exchange material is a polymeric anion or cation exchange material.
  • the choice of the appropriate second polymeric ion exchange resin is determined by the acid/base properties of the resin.
  • the second polymeric anion or cation exchange material is a polymeric anion or cation exchange resin. In other embodiments, the second polymeric anion or cation exchange material is a polymeric anion or cation exchange membrane.
  • Suitable second polymeric cation exchange resins comprise, for example, polacrilin, acrylate, methyl sulfonate, methacrylate, carboxylic acid functional groups, sulfonic acid, sulfoisobutyl, or sulfoxyethyl.
  • the second polymeric cation exchange resin comprises polacrilin or acrylate.
  • Suitable second polymeric cation exchange resins comprise, for example, a polymer having one or more acid moieties.
  • Such polymers include, for example, polyacrylic acids, polyacrylic sulfonic acids, polyacrylic phosphoric acids and polyacrylic glycolic acids.
  • anion exchangers those ion exchange materials identified as weak anion are preferred.
  • Several such polymers are available within the "Bio-Rex" and "AG” family of resins from Biorad (i.e. Bio-Rex 5 and AG 4-X4).
  • Other anion exchange materials include forms of Amberlite (available from Rohm and Haas), e.g., Amberlite IRA67.
  • Further anion exchange resins include the "Dowex" family of resins from Dow Chemicals (Dowex Monosphere 77).
  • the degree of neutralization of the second ion exchange resin in the formulations prepared according to certain embodiments of the methods of the invention, and the concentration of the second ion exchange resin, are spread over a range of values.
  • the degree of neutralization of the second polymeric anion or cation exchange resin is about 2 % to about 70 %. In more preferred embodiments, the degree of neutralization of the second polymeric anion or cation exchange resin is about 5 % to about 50 %. In even more preferred embodiments, the degree of neutralization of the second polymeric anion or cation exchange resin is about 5 % to about 30 %.
  • the concentration of the second polymeric anion or cation exchange resin in the formulations prepared according to certain embodiments of the methods of the invention is about 20 meq/mL to about 200 meq/mL. In more preferred embodiments, the concentration of the second polymeric anion or cation exchange resin is about 20 meq/mL to about 140 meq/mL. In even more preferred embodiments, the concentration of the second polymeric anion or cation exchange resin is about 25 meq/mL to about 60 meq/mL.
  • the lower end of the percentage of the second ion exchange resin is preferred because it adds the least amount of competing sodium ions to the formulation. Furthermore, at lower concentrations, adverse effects in achieving steady state flux are avoided with shorter rise time to attain steady state flux.
  • the drug is a 2-[3-[4-(4-piperidinyloxy)anilino]-1propenyl]benzamidine derivative and the second ion exchange resin is polacrilin.
  • the desired amount of the polacrilin in the formulations prepared according to such embodiments of the methods of the invention is about 0.23 % to about 1.13 %, neutralized to between about 5 % to about 10 %.
  • this range would narrow down to about 0.23 % to about 0.40 % of the second anion exchange resin, neutralized to between about 5 % and 8 %.
  • the reservoir of the electrotransport delivery devices generally comprises a gel matrix, with the drug solution uniformly dispersed in at least one of the reservoirs.
  • Suitable polymers for the gel matrix can comprise essentially any nonionic synthetic and/or naturally occurring polymeric materials. A polar nature is preferred when the active agent is polar and/or capable of ionization, so as to enhance agent solubility.
  • the gel matrix can be water swellable.
  • suitable synthetic polymers include, but are not limited to, poly(acrylamide), poly(2-hydroxyethyl acrylate), poly(2-hydroxypropyl acrylate), poly(N-vinyl-2-pyrrolidone), poly(n-methylol acrylamide), poly(diacetone acrylamide), poly(2-hydroxylethyl methacrylate), poly(vinyl alcohol) and poly(allyl alcohol).
  • Hydroxyl functional condensation polymers i.e., polyesters, polycarbonates, polyurethanes
  • suitable polar synthetic polymers are also examples of suitable polar synthetic polymers.
  • Polar naturally occurring polymers (or derivatives thereof) suitable for use as the gel matrix are exemplified by cellulose ethers, methyl cellulose ethers, cellulose and hydroxylated cellulose, methyl cellulose and hydroxylated methyl cellulose, gums such as guar, locust, karaya, xanthan, gelatin, and derivatives thereof.
  • Ionic polymers can also be used for the matrix provided that the available counterions are either drug ions or other ions that are oppositely charged relative to the active agent.
  • the reservoir of the electrotransport delivery system comprises a hydrogel. In other embodiments of the invention, the reservoir comprises a non-hydrogel, dry matrix.
  • the reservoir of the electrotransport delivery system comprises a polyvinyl alcohol hydrogel as described, for example, in U.S. Patent No. 6,039,977 , incorporated herein by reference in its entirety.
  • Polyvinyl alcohol hydrogels can be prepared, for example, as described in U.S. Patent No. 6,039,977 .
  • the weight percentage of the polyvinyl alcohol used to prepare gel matrices for the reservoirs of the electrotransport delivery devices, in certain embodiments of the methods of the invention is about 10 % to about 30 %, preferably about 15 % to about 25 %, and more preferably about 19 %.
  • Incorporation of the drug solution into the gel matrix can be done any number of ways, i.e., by imbibing the solution into the reservoir matrix, by admixing the drug solution with the matrix material prior to hydrogel formation, or the like.
  • the solution is incorporated into the drug reservoir, e.g., a gel matrix as just described, and is then administered to a patient using an electrophoretic drug delivery system.
  • the second ion exchange material serves to reduce changes in the pH of the drug reservoir, and to maintain the desired pH of the reservoir, during electrotransport, resulting in greater stability and enhanced delivery of the drug.
  • a pH-adjusted drug solution is contacted with a second ion exchange material, and the solution is then stored, rather than being incorporated into the reservoir of an electrotransport delivery device for administration to a patient.
  • the second ion exchange material serves to reduce changes in the pH of the drug solution and to maintain the desired pH of the solution during long-term storage.
  • Drug solutions formulated according to the methods of the invention can thus be stably stored for extended periods of time such as, for example, weeks to months to years.
  • a pH-adjusted drug solution is introduced into the reservoir of an electrotransport delivery system, and is contacted with a second ion exchange material, either before or after incorporation into the reservoir. Instead of being used immediately, the reservoir is stored for an extended period of time.
  • the second ion exchange material serves to reduce changes in the pH of the reservoir and to maintain the desired pH of the reservoir during storage. Reservoirs containing a pH-adjusted drug solution prepared according to the methods of the invention can be stably stored for extended periods of time such as, for example, weeks to months to years.
  • Hydrogels were typically prepared by placing polyvinyl alcohol (PVOH) at 19 wt % in purified water at 90°C for 30 minutes, reducing the temperature to 50°C, dispensing the gel suspension into disks, and freeze-curing. The formed hydrogels were then allowed to imbibe the pH-adjusted drug solution as a concentrated aqueous solution at room temperature to obtain the desired drug loading. Alternatively, drug loading was achieved by adding the pH-adjusted solution of the drug to the PVOH hydrogel solution before freezing. In the thermally processed formulations, PVOH was dissolved in purified water at 90°C.
  • PVOH polyvinyl alcohol
  • hydrogels prepared as described above and containing polacrilin and Compound 1 were stored at 4°C, 25°C, or 40°C for 12 weeks and the pH of the hydrogels were determined each week.
  • Figure 3 shows the changes in the pH of the hydrogels that occurred over time, and demonstrates that the polacrilin served to buffer the hydrogels during storage.
  • the pH of an anionic drug is adjusted with a polymeric cation exchange material and is then buffered with a polymeric ion exchange material according to the following procedure.
  • the drug ceftriaxone (supplied as the disodium salt) has the following three pKa's: 3 (carboxylic), 3.2 (amine), and 4.1 (enolic OH), which act as bases in solution. Using the Henderson-Hasselbach equation, the theoretical final pH of this system can be calculated.
  • a polymeric cation exchange material is added to a solution of ceftriaxone to adjust the pH of the solution to a value between that of the second and third pKa's of the drug.
  • An appropriate polymeric ion exchange material with an appropriate pKa is then used to buffer the solution to maintain the pH during storage and/or operation of an electrotransport device

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Claims (25)

  1. Verfahren zur Herstellung einer Zusammensetzung zur Verwendung in einem Elektrotransportabgabesystem umfassend
    Bereitstellen einer Arzneimittellösung, die Arzneimittelionen und zugehörige Gegenionen aufweist;
    Einstellen:des pH-Wertes der Arzneimittellösung durch in Kontakt bringen der Arzneimittellösung mit einem ersten lonenaustauchmaterial;
    Trennen des ersten lonenaustauschmaterials von der Arzneimittellösung mit eingestelltem pH-Wert;
    Hinzufügen der pH-Wert eingestellten Arzneimittellösung in ein Reservoir eines Elektrotransportabgabesystems; und
    in Kontakt bringen der Lösung eingestelltem pH-Wert mit einem zweiten lonenaustauschmaterial.
  2. Verfahren nach Anspruch 1, bei dem das Reservoir des Elektrotransportabgabesystems eine Gelmatrix umfaßt.
  3. Verfahren nach Anspruch 2, bei dem die Gelmatrix Poly(acrylamid), Poly(2-hydroxylethylacrylat), Poly(2-hydroxypropylacrylat), Poly(N-vinyl-2-pyrrolidon), Poly(n-methylolacrylamid), Poly(diacteonacrylamid), Poly(hydroxylethylmeth-acrylat), Poly(vinylalkohol), Poly(allylalkohol), Polyester, Polycarbonate, Polyharnstoffe, Celluloseether, Methylcelluloseether, Cellulose und hydroxylierte Cellulose, Methylcellulose, hydroxylierte Methylcellulose, Guaran, Johannisbrotgummi, Karayagummi, Xanthan, Gelatine oder deren Derivate umfaßt.
  4. Verfahren nach Anspruch 3, bei dem Gelmatrix Poly(vinylalkohol) umfaßt.
  5. Verfahren nach einem der vorherigen Ansprüche, bei dem die Arzneimittelionen kationisch sind, die zugehörigen Gegenionen anionisch sind und das erste lonenaustauschmaterial ein erstes polymeres Anionenaustauschmaterial ist.
  6. Verfahren nach einem der vorherigen Ansprüche, bei dem die Arzneimittelionen kationisch sind, die zugehörigen Gegenionen anionisch sind und das erste lonenaustauschmaterial ein ersten polymeres Anionenaustauschmaterial ist und bei dem Hydroxylionen durch die anionischen Gegenionen, die mit den kationischen Arzneimittelionen verbunden sind, ausgetauscht werden, wenn die Arzneimittellösung mit dem ersten polymeren Anionenaustauschmaterial in Kontakt gebracht wird.
  7. Verfahren nach einem der vorherigen Ansprüche, bei dem der pH-Wert der Arzneimittellösung zwischen pH 3 und pH 9 eingestellt wird.
  8. Verfahren nach einem der vorherigen Ansprüche, bei dem das erste polymere lonenaustauchmaterial ein erstes polymeres Anionenaustauschharz ist.
  9. Verfahren nach einem der vorherigen Ansprüche, bei dem das erste polymere lonenaustauschmaterial ein erstes polymeres Anionenaustauschharz ist, daß eine Hydroxidform eines aminhaltigen Polymers aufweist.
  10. Verfahren nach Anspruch, 9 bei dem das aminhaltige Polymer ausgewählt wird aus der Gruppe, bestehend aus Polyvinylaminen, Polyepichlorhydrin/Tetraethylentriaminen, Copolymeren aus Styrol und Divinylbenzol, Acryl/Divinylbenzolcopolymeren und Acryl/Ethylenglykoldimethacrylatcopolymeren.
  11. Verfahren nach einem der vorherigen Ansprüche, bei dem das erste polymere lonenaustauschmaterial eine erste polymere Anionenaustauschmembran ist.
  12. Verfahren nach einem der vorherigen Ansprüche, bei dem das zweite lonenaustauschmaterial ein zweites polymeres Anionen- oder Kationenaustauschharz ist
  13. Verfahren nach einem der vorherigen Ansprüche, bei dem das zweite Ionenaustauschmaterial ein zweites polymeres Ionenaustauschharz ist, umfassend Polacrilin, Acrylat, Methylsulfonat, Methylacrylat, funktionelle CarbonsäureGruppen, Sulfonsäure, Sulfoisobutyl oder Sulfoxyethyl.
  14. Verfahren nach einem der vorherigen Ansprüche, bei dem das zweite lonenaustauschharzmaterial Polacrilin oder Acrylat aufweist.
  15. Verfahren nach einem der vorherigen Ansprüche, bei dem das zweite lonenaustauschmaterial ein zweites polymeres Kationenaustauschharz ist, umfassend Polyacrylsäure, Polyacrylsulfonsäure, Polyacrylphosphorsäure oder Polyacrylglykolsäure.
  16. Verfahren nach Anspruch 12, bei dem der Neutralisationsgrad des zweiten polymeren Anionen- oder Kationenaustauschharzes 2% bis 70% beträgt.
  17. Verfahren nach Anspruch 12, bei dem die Konzentration des zweiten polymeren Anionen- oder Kationenaustauschharzes 20 meq/ml bis 200 meq/ml beträgt.
  18. Verfahren nach Anspruch 12, bei dem der Neutralisationsgrad des zweiten polymeren Anionen- oder Kationenaustauschharzes 2% bis 70% beträgt und die Konzentration des zweiten polymeren Anionen- oder Kationenaustauschharzes 20 meq/ml bis 200 meq/ml beträgt.
  19. Verfahren nach einem der vorherigen Ansprüche, bei dem die Arzneimittellösung kationische Arzneimittel enthält, das ein Faktor Xa-Inhibitor und eine Anticoagulans ist.
  20. Verfahren nach Anspruch 19, bei dem das kationische Arzneimittel ein Benzamidinderivat ist.
  21. Verfahren nach einem der vorherigen Ansprüche, bei dem die Arzneimittelionen anionisch:sind, die zugehörigen Gegenionen kationisch sind und das erste lonenaustauschmaterial ein erstes polymeres Kationenaustauschmaterial ist.
  22. Verfahren nach einem der vorherigen Ansprüche, bei dem die Arzneimittellösung anionische Ameimittelionen enthält, Hydroniumionen werden durch kationische Gegenionen, die mit den anionischen Arzneimittelmittelionen verbunden sind, ausgetauscht, wenn die Arzneimittellösung mit dem ersten Anionenaustauschmaterial in Kontakt gebracht wird.
  23. Verfahren nach einem der vorherigen Ansprüche, bei dem das erste lonenaustauschmaterial ein Polymer umfaßt, das eine oder mehrere Säureanteile hat.
  24. Verfahren nach einem der vorherigen Ansprüche, bei dem die Arzneimittellösung eine wässerige Lösung ist.
  25. Verfahren nach einem der vorherigen Ansprüche, bei dem das erste lonenaustauschmaterial von der Lösung mit eingestelltem pH-Wert durch Filtration oder Zentrifugation entfernt wird.
EP04811757A 2003-11-19 2004-11-19 Verfahren zur herstellung von polymeren pufferformulierungen für elektrotransport-anwendungen Not-in-force EP1684851B1 (de)

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PCT/US2004/039096 WO2005051484A1 (en) 2003-11-19 2004-11-19 Methods for preparing polymeric buffer formulations for electrotransport applications

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UY28935A1 (es) 2004-06-03 2005-07-29 Alza Corp Sistema y metodo para la administracion transdermica de un anticoagulante
US20070225632A1 (en) * 2006-03-21 2007-09-27 David Rauser Hydratable polymeric ester matrix for drug electrotransport
EP2101864A2 (de) * 2006-12-20 2009-09-23 ALZA Corporation Anode für den elektrischen transport eines kationischen arzneimittels
US20090105632A1 (en) * 2007-10-18 2009-04-23 Padmanabhan Rama V Electrotransport Of Lisuride

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US5080646A (en) * 1988-10-03 1992-01-14 Alza Corporation Membrane for electrotransport transdermal drug delivery
US5147296A (en) * 1988-10-03 1992-09-15 Alza Corporation Membrane for electrotransport transdermal drug delivery
US5169382A (en) * 1988-10-03 1992-12-08 Alza Corporation Membrane for electrotransport transdermal drug delivery
US5853383A (en) * 1995-05-03 1998-12-29 Alza Corporation Preparation for formulations for electrotransport drug delivery
WO1997012644A1 (en) * 1995-09-29 1997-04-10 Becton Dickinson And Company Improved iontophoretic reservoir apparatus
AU1302499A (en) * 1997-11-12 1999-05-31 Alza Corporation Buffered drug formulations for transdermal electrotransport delivery
US6039977A (en) * 1997-12-09 2000-03-21 Alza Corporation Pharmaceutical hydrogel formulations, and associated drug delivery devices and methods
WO2002089803A1 (en) * 2001-05-07 2002-11-14 Sankyo Company, Limited Composition for iontophoresis

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DK1684851T3 (da) 2008-01-07
CA2546405A1 (en) 2005-06-09
US20050129655A1 (en) 2005-06-16
PT1684851E (pt) 2007-12-03
DE602004008502T2 (de) 2008-01-03
KR20070001877A (ko) 2007-01-04
EP1689489B1 (de) 2008-02-27
ATE387240T1 (de) 2008-03-15
JP2007516962A (ja) 2007-06-28
JP2007511617A (ja) 2007-05-10
EP1689489A1 (de) 2006-08-16
WO2005051484A1 (en) 2005-06-09
DE602004012143T2 (de) 2008-06-19
EP1684851A1 (de) 2006-08-02
CA2546399A1 (en) 2005-06-09
ATE370766T1 (de) 2007-09-15
WO2005051485A1 (en) 2005-06-09
DE602004008502D1 (de) 2007-10-04
US20050142531A1 (en) 2005-06-30
KR20060130042A (ko) 2006-12-18
ES2291975T3 (es) 2008-03-01
PL1684851T3 (pl) 2007-12-31

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